The regulation of blood vessel growth has been our major focus for the last 18 years. At that time, we reported that high blood pressure in animal models and humans is associated with a rarefaction of small arterioles. This led us to propose the hypothesis that the long-term regulation of vascular resistance is manifested by a change in the number of arterioles per unit volume of tissue, whereas the short-term regulation of vascular resistance is brought about by alterations in vessel diameter. The control of neovascularization or angiogenesis is very important in the maintenance of cardiovascular health and has been implicated in the initiation or repair of many cardiovascular pathophysiologies (e.g, aging, hypertension, myocardial ischemia, stroke, peripheral vascular disease, diabetes, wound healing, inflammation, and cancer). Specifically, we plan to investigate the role of local autoregulatory agents and calcium in the long-term regulation of blood vessel growth. These experiments will be accomplished by local and systemic application of modulators of adenosine and calcium. We further propose to study the differential effects of hypertension and aging on arteriolar rarefaction and venular proliferation, by the systemic application of agents which are known to alter capillary pressure and wall stress. Additionally, we plan to observe for systemic hemodynamic effects in our computerized, chronic monitoring facility. It is important to investigate the systemic application of these agents over several weeks (or months in some cases) in order to document both potential long-term local vasoactivities and the systemic hemodynamic effects. Where possible, we will leave the animal connected to the hemodynamic monitoring apparatus while performing the assessment of microvessel response. This innovative technique allows us to insure that the assessment procedure itself does not alter cardiovascular status. The cerebral and skeletal muscle circulations are two of the most important in the body. Fortunately, "windows" into these microcirculations have been developed which allow long-term monitoring of the alterations produced in these blood vessels. We plan to evaluate the angiogenic and anti-angiogenic potential of the aforementioned interventions on these two microvasculatures. Chronic preparations are very useful for this type of assessment in that they allow following the same vascular beds and vessels over a long period of time, thus greedy reducing statistical variance and permitting more accurate conclusions to be reached. These experiments utilize unique and innovative concepts and techniques to determine the important role of microvessel growth regulation in health and disease.